Minimizing progestin associated breakthrough bleeding

ABSTRACT

A method for minimizing menstrual bleeding irregularities in individuals using progestin-only pharmaceutical preparations, such as contraceptives, is disclosed.

FIELD OF THE INVENTION

The invention relates to compositions and methods for minimizingbreakthrough bleeding in users of progestin-only pharmaceuticpreparations, such as contraceptives.

BACKGROUND OF THE INVENTION

The primate menstrual cycle is characterized by a proliferation andregression of the uterine lining under the control of steroid hormones,primarily estrogen and progesterone. It is believed that the staggeredcyclic levels of hormones contribute to the growth and shedding of theupper tissue compartment of the uterus.

The endometrium on the uterus is characterized by distinct layers, suchas the stratum functionalis and stratum basalis. It is the functionaliswhich represents the transient upper tissue compartment that is shedduring menstruation.

It is believed that the basalis serves as a source of new cells for theregeneration of the functionalis in succeeding cycles. Wilborn &Flowers, Seminars in Reproductive Endocrinology 2:4, 307, 1984; Padykulaet al., Biology of Reproduction 40, 681, 1989. If the basalis does serveas a germinal layer, then the effects of damage to the basalis during agiven cycle could be manifest in succeeding cycles.

Because endometrial proliferation serves to prepare the uterus for animpending pregnancy, manipulation of hormones and of the uterineenvironment can serve as suitable targets for contraception. Forexample, estrogens are known to decrease follicle stimulating hormonesecretion by feedback inhibition.

Under certain circumstances, estrogens can also inhibit luteinizinghormone secretion, once again by negative feedback, although undernormal circumstances it is believed that the spike of circulatingestrogen found just prior to ovulation induces the surge ofgonadotrophin hormones that occurs just prior to and resulting inovulation. High doses of estrogen also can prevent conception probablydue to interference with implantation.

Progesterone is responsible for the progestational changes of theendometrium and the cyclic changes of cells and tissues in the cervixand the vagina. For example, progesterone makes the cervical mucusthick, tenacious and cellular. It is believed that thickened mucusimpedes spermatozoal transport.

Progesterone has somewhat of an anti-estrogenic effect on the myometrialcells, for example, decreasing the excitability of the smooth musclecells, and the like. It is known that large doses of progesteroneinhibit luteinizing hormone secretion and progesterone injections canprevent ovulation in humans.

The most prevalent form of oral contraception is a pill that combinesboth an estrogen and a progestagen, the so-called combined oralcontraceptive preparations. Apparently, the estrogen and progestagen actin concert to block gonadotrophin release.

Alternatively, there are oral contraceptive preparations that comprise aprogestagen only. Such preparations are indicated particularly forindividuals who have experienced side effects or an intolerance to thecombined preparations or in lactating women because of the lack of anestrogenic effect on lactation.

However, the progestagen-only preparations have a more varied spectrumof side effects than do the combined preparations. A disadvantage of theprogestagen-only preparations is the relatively high incidence ofbleeding problems, such as, prevalent or heavier menstrual spotting,amenorrhea and more breakthrough bleeding. Thus, the combinedpreparations are the preferred oral contraceptives in use today. Shethet al., Contraception 25,243, 1982.

Some of the very common side effects of the progestagen-only oralcontraceptives is the increased incidence of menstrual spotting, break.through bleeding, variations in menstrual cycle length and occasionallyamenorrhea.

Nevertheless, it would be preferable to have an contraceptivepreparation that minimizes the amounts of estrogens and progestagensused. For example, estrogens are known to cause dizziness, nausea,headache and breast tenderness. Thus, a progestagen-only contraceptivewould forego such possible problems and be an improvement over thecombined preparations if the above-referred to problems ofprogestagen-only contraceptives also can be remedied. George WashingtonUniversity Medical Center, Population Reports, Series A, No. 3,September 1975.

Anti-progestins include inhibitors of progesterone synthesis, ligands,such as antibodies, to progesterone and progesterone receptorantagonists. For example, mifepristone (RU486) is a progesteronereceptor antagonist. RU486 binds to the progesterone receptor andproduces antagonistic effects. Following oral administration, RU486 inthe human has a half life of about 20-24 hours. When administered in theluteal phase of the menstrual cycle, RU486 induces luteolysis andvaginal bleeding.

RU486 may act directly on the endometrium to induce vaginal bleeding.RU486-mediated luteolysis appears to be secondary to changes ingonadotrophin secretion and thus the effects are similar to thosefollowing exogenous progesterone administration. Baulieu, Science 245,1351, 1989.

Swahn et al. (Human Reproduction 5(4), 402, 1990) relates toadministering RU486 early during the luteal phase prior to implantation.Those authors found that a single dose of RU486 administered on thesecond day after the LH peak causes a retardation of endometrialdevelopment, without upsetting the menstrual cycle. Those authorsspeculated that it may be possible that the effect on the endometriummay be sufficient to prevent implantation.

SUMMARY OF THE INVENTION

It is an object of the instant invention to provide a method and meansof enhancing the value progestin-only pharmaceutical preparations, suchas contraceptives.

It is another object of the instant invention to provide a kit and/orprogram to enhance the every day use of progestin-only pharmaceuticalpreparations, such as contraceptives.

Those and other objects have been achieved in the development of amethod for minimizing uterine bleeding in a female using aprogestin-only pharmaceutical preparation comprising administering tosaid female a biologically effective amount of an anti-progestin.

The invention also relates to a method of birth control comprisingadministering to a female a composition comprising biologicallyeffective amounts of a progestin and an anti-progestin.

Further, the invention relates to a contraceptive composition comprisinga progestin and an anti-progestin.

The invention also relates to an implant intended for subcutaneous orlocal administration comprising a pharmaceutically acceptable inert corematerial which would function as a matrix, a progestin and ananti-progestin.

The invention further relates to a kit. comprising a plurality of pillsor tablets to be administered sequentially at one per day, wherein saidpills or tablets are placebos except for an active agent-containing pillor tablet comprising an anti-progestin.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts the breakthrough bleeding rate per monkey over the courseof treatment. Individual monkeys were given a progestin-onlycontraceptive and intermittent dosing of anti-progestin. Breakthroughbleeding was scored on all days except for the seven days following anRU486 dose. The average duration of bleeding following an RU486.dose was3.2±1.1 days. The incidence of RU486-induced menses was 100% within 72hours. Open bars indicate monkeys receiving oral contraceptive,levonorgestrel, only. Stippled bars represent monkeys receivinglevonorgestrel and RU486 at days 30, 60, 90, 120, 150 and 180.Cross-hatched bars indicate monkeys receiving levonorgestrel and RU486at days 90 and 180. The daily dose of levonorgestrel was 10 μg per dayorally except on the day when RU486 was given when no progestin wasadministered. RU486 was administered orally and intermittently at 50 mgper dose.

FIG. 2 depicts serum estradiol and progesterone levels in monkeys of thevarious treatment groups. The lower limit of detection of estradiol was12 pg/ml. The lower limit of detection of progesterone was 0.2 ng/ml.The top panel depicts animals receiving progestin only on a daily basis.The middle panel depicts animals receiving progestin daily and RU486 ondays 30, 60, 90 and 120. The bottom panel depicts animals receivingprogestin daily and RU486 on day 90 only. The progestin waslevonorgestrel.

DETAILED DESCRIPTION OF THE INVENTION

The instant invention relates to a method and means for reducingirregular bleeding in those users of progestagen-only pharmaceuticalpreparations, such as contraceptives. The invention relates to the useof an anti-progestin in combination with the progestagen-onlypharmaceutical preparations, such as a contraceptive. For the purposesof the instant invention, progestin and progestagen are consideredsynonyms.

Progestagen-only pharmaceutical preparations, such as tablets which canbe administered orally, vaginal rings, implant systems (biodegradable ornot), injectables and transdermal systems, which can be used ascontraceptives are known in the art.

For example, commonly used oral contraceptives contain the syntheticprogestins, cingestol, ethynodiol diacetate, lynestrenol, norethindrone,norgestrel, quingestanol acetate, levonorgestrel (active ingredient ofNORPLANT), norethisterone, chlormadinone, megestrol, desogestrel,gestodene, norgestimate and the like. Fotherby, Journal of DrugDevelopment 4 (2), 101, 1991. Essentially any progestin suitable for usein a progestagen-only pharmaceutical can be used in the practice of theinstant invention.

The anti-progestin can be an inhibitor of progesterone synthesis, suchas epostane, azastene or trilostane (Creange, Contraception 24, 289,1981; Drugs of the Future 7, 661, 1982; van der Spuy et al., Clin. Endo.19, 521, 1983; Birgerson et al., Contraception 35, 111, 1987; U.S. Pat.No. 3,296,255) or a progesterone receptor antagonist, or any suchpharmaceutically suitable agent that counteracts the normal biologicalactivity of progesterone, such as antibodies or ligands bindable toprogestins or to the progesterone receptor.

A suitable anti-progestin is a progesterone receptor antagonist. Forexample, RU486, Onapristone, Org 31710((6α,11β,17β)-11-(4-dimethylaminophenyl)-6-methyl-4',5,'-dihyrospiro[estra-4,9-diene-17,2'(3'H)-furan]-3-one), Org 33628((11β,17α)-11-(4-acetylphenyl)-17,23-epoxy-19,24-dinorchola-4,9,20-trien-3-one)and Org 31806 ( (7β,11β,17β)-11-(4-dimethylaminophenyl-7-methyl-4',5'-dihydrospiro[estra-4,9-diene-17,2'(3'H)-furan]-3one) are particularlysuitable in the practice of the instant invention. U.S. Pat. No.4386085.

The anti-progestin can be administered by way of any art-recognizedmeans practiced in the pharmaceutic arts. For example, a suitableanti-progestin may be so formulated so that it can be administeredorally, via a skin patch for transdermal absorption, contained within aninert matrix which is implanted within the body and in the implantedstate is released slowly, such an implant is taught in U.S. Pat. Nos.4,957,119 and 5,088,505 and the like.

Thus, pharmaceutic formulations of solid dosage forms include tablets,capsules, cachets, pellets, pills, powders or granules; topical dosageforms include solutions, powders, fluid emulsions, fluid suspensions,semi-solids, ointments, pastes, creams, gels or jellies and foams; andparenteral dosage forms includes solutions, suspensions, emulsions or adry powder comprising an effective amount of anti-progestin as taught inthe instant invention.

It is known in the art that the active ingredient, the anti-progestin,can be contained in such formulations in addition to pharmaceuticallyacceptable diluents, fillers, disintegrates, binders, lubricants,surfactants, hydrophobic vehicles, water soluble vehicles, emulsifiers,buffers, humectants, moisturizers, solubilizers, preservatives and thelike. The means and methods for administration are known in the art andan artisan can refer to various pharmacologic references for guidance,see, for example, "Modern Pharmaceutics" Banker & Rhodes, Marcel Dekker,Inc. 1979; "Goodman & Gilman's The Pharmaceutical Basis ofTherapeutics", 6th Edition, MacMillan Publishing Co., New York 1980.

In the case of oral contraceptives, it is known that the kits thereofcontain a pill for each day of the month (either 28 days, the lunarmonth, or 30 days) wherein any one pill may be a placebo or may containone or more of the active ingredients.

The effective amount of an anti-progestin in the practice of the instantinvention can be determined using art-recognized methods, for example,by establishing dose-response curves in suitable animal models andextrapolating therefrom to humans, extrapolating from suitable in vitrosystems or by determining effectiveness in clinical trials. Thedetermination of an effective dose is a routine exercise in thepharmaceutic arts. The artisan will take into account various physicalparameters of the prospective host such as weight, age and the like.

In like vein, the dosage regimen of the preparation is determinableusing art-recognized methods such as establishing a dose response curvein similar primate models or in a suitable in vitro experimental systemor by an empirical determination in clinical trials.

It is contemplated, in view of the dynamic state of the endocrine systemin primates, that administration of the anti-progestin can be either ona tonic or continuous basis, such as in parallel with administration ofa progestin-only oral contraceptive, or on an episodic basis because ofthe dynamic relationship of the endometrial cells and the long termeffects of anti-progestins. Thus, the anti-progestin can be administeredin combination with the progestin in the form of a pill or as aco-component in an implant or the progestin can be given in one form andthe anti-progestin can be given in another form, for example, theprogestin may be given in the form of a pill and the anti-progestin canbe delivered as a component of an implant. Alternatively, the progestincan be administered daily whereas the anti-progestin is administeredmonthly, or at other intermittent intervals.

In the case of the progesterone receptor antagonists RU486, Org 33628,Org 31806 and Org 31710, it is anticipated that a suitable human oraldose will be on the order of 10-250 mg per dose. The amount per dose canbe lowered or raised based on the number of doses actually given, thatis the interval at which the doses of anti-progestin are administeredand characteristics of the individual receiving the treatment and thepotency of a particular anti-progestin.

The number of doses can vary from monthly to longer intervals takinginto consideration cost, safety and the like. Thus, a suitable regimenis having the anti-progestin administered every thirty days, every sixtydays or every ninety days. Alternatively, in the case of contraceptiveswhere many of the pill kits are configured based on the lunar month, theanti-progestin can be administered on the twenty-eighth day of eachcycle. Variations of dosage based on route of administration may varyand such changes can be determined practicing known techniques asdescribed above.

All references cited herein are herein incorporated by reference.

The present invention is described further below with respect tospecific examples which are tended to illustrate the instant inventionwithout limiting the scope thereof.

EXAMPLE

In the present study, laboratory primates (Macaca fasicularis, n=18),having normal ovulatory menstrual cycles, were assigned at random to oneof three groups: Group I (n=6) received 10 μg of levonorgestrel daily byoral ingestion for 180 days. Group II (n=6) was given the same doseregimen of levonorgestrel as in Group I, except that 50 mg of RU486 wasadministered orally and intermittently on treatment days 30, 60, 90,120, 150 and 180. Similarly, Group III primates (n=6) receivedlevonorgestrel daily, but RU486 on treatment days 90 and 180. For GroupsII and III, levonorgestrel was withheld only on the days that theanti-progestin was given.

Breakthrough bleeding was recorded daily based on presence or absence ofblood in the vagina upon insertion of a saline-moistened cotton-tippedapplicator. Menstrual bleeding that occurred within 7 days after eachRU486 treatment was not counted as breakthrough bleeding.

To determine whether the dose of levonorgestrel reliably blockedovulation, all primates were bled daily from the femoral vein (3.0 ml)from treatment day 91 to 120, so that serum estradiol and progesteronelevels could be determined by radioimmunoassay using known materials andtechniques.

Intermittent RU486 treatment in animals receiving a progestin dailymarkedly reduced irregular menstrual bleeding by 69% on average, whetherthe interval between treatments of the anti-progestin was 30 or 90 days(p<0.05). However, there was a trend (p>0.05) toward rising breakthroughbleeding in the 2nd and especially 3rd month after RU486 treatment(Group III).

That the daily dose regimen of levonorgestrel effectively blockedovulation was evident from the absence of overt serum progesteroneelevations. The intermittent doses of anti-progestin did suppresstransiently mean tonic serum estradiol to below 30 pg/ml for four orfive days; otherwise ovarian estrogen secretion was non-episodic (48±11pg/ml, Group I; 41±6 pg/ml, Group II; and 42±9 pg/ml; Group III).

More importantly, intermittent administration of RU486 significantlyreduced irregular menstrual bleeding whether the every 30 day or every90 day anti-progestin regimen was employed, albeit the anti-progestinimpact appeared to fade with less frequent dosing.

The bleeding control effect of RU486 was manifest for two to threemonths. The anti-progestin may have imparted certain long-lastingfunctional characteristics in basal endometrial cells. The primate datashow the effectiveness of combining progestin with an anti-progestin,without the need for exogenous estrogen, to control endometrialbleeding.

It should be noted that the efficacy of the progestin to block ovulationis not compromised by the intermittent administration of ananti-progestin. See FIG. 2.

While the invention has been described in detail and with reference tocertain embodiments thereof, it would be apparent to one skilled in theart that various changes and modifications can be made without departingfrom the spirit and scope thereof.

What is claimed:
 1. A method for minimizing uterine bleeding in a femaleusing a progestin-only pharmaceutical preparation comprisingadministering to said female a biologically effective amount of ananti-progestin.
 2. The method of claim 1, wherein said anti-progestin isa compound that inhibits progesterone synthesis or is a progesteronereceptor antagonist.
 3. The method of claim 2, wherein said antagonistis selected from the group consisting RU486, Org 33628, Org 31806 andOrg
 31710. 4. The method of claim 3, wherein said antagonist isadministered in a dose of about 10 mg to about 250 mg per dose.
 5. Themethod of claim 3, wherein said antagonist is administered once every 30days.
 6. The method of claim 3, wherein said antagonist is administeredonce every 60 days.
 7. The method of claim 3, wherein said antagonist isadministered once every 90 days.
 8. The method of claim 3, wherein saidantagonist is administered on the 28th day of a cycle.
 9. The method ofclaim 1, wherein said progestin is desogestrel.
 10. The method of claim1, wherein said progestin and said anti-progestin are administeredconcurrently.
 11. The method of claim 1, wherein said anti-progestin isadministered in the form of a pill or tablet.
 12. The method of claim 1,wherein said anti-progestin is administered as a component of animplant.
 13. A method of minimizing breakthrough bleeding associatedwith a progestin-only birth control method comprising administering to afemale a composition comprising an amount of a progestin suitable forcontraception and an anti-progestin in an amount which minimizesbreakthrough bleeding.
 14. A progestin-only contraceptive compositionwith minimal breakthrough bleeding comprising a progestin and ananti-progestin in an amount which minimizes breakthrough bleeding. 15.The composition of claim 14, wherein said progestin is desogestrel. 16.The composition of claim 14, wherein said anti-progestin is selectedfrom the group consisting of RU486, Org 33628, Org 31710 and Org 31806.17. The composition of claim 14, wherein said progestin is desogestreland said anti-progestin is Org
 31710. 18. A progestin-only contraceptiveimplant intended for subcutaneous or local administration with minimalbreakthrough bleeding comprising a pharmaceutically acceptable inertcore material which would function as a matrix, a progestin and ananti-progestin in an amount which minimizes breakthrough bleeding.
 19. Aprogestin-only contraceptive kit comprising a plurality of pills ortablets to be administered sequentially at one per day, wherein saidpills or tablets are placebos or contain a progestin except for anactive agent-containing pill or tablet comprising an anti-progestin inan amount which minimizes breakthrough bleeding.
 20. The kit of claim19, wherein said kit comprises at least 28 pills or tablets and saidactive agent-containing pill or tablet is administered on the 28th day.21. The kit of claim 19, wherein said kit comprises at least 30 pills ortablets and said active agent-containing pill or tablet is administeredon the 30th day.